The molecular basis of corneal neovascularization and corneal surface disease are still poorly understood. Current experimental models available for the study of these diseases often rely on external stimuli-trauma that may not reflect the mechanisms of spontaneous disease. A recently described mutant, corn1, provides the first animal model of genetically determined, spontaneous corneal epithelial disease and neovascularization. These animals can provide a reproducible source of tissue for biochemical studies and for elucidation of the pathways involved in these processes. Corn1 mouse develops focal hyper-proliferation of the corneal epithelium, followed by neovascularization. These features remain constant and do not regress. Eventually, corn1 mice develop cortical cataracts. A second spontaneous mutation in the corn1 locus, corn1/2J, on a different genetic background, demonstrates a mild epithelial phenotype, with no neovascularization. The overall goal of the proposed research is to gain insights into the relationship between epithelial proliferation and neovascularization in corn1 and corn1/2J mice, to assess the presence or absence of suppressors or enhancers of proliferation and angiogenesis, and to determine if there are common or different molecular biological mechanisms regulating these phenomena. Specifically, at the successful conclusion of this project, the molecular basis of corn1 and corn1/2J will be identified through a positional cloning strategy. In addition, through genetic cross, the nature of a new allele, corn1/2J, will be evaluated to determine the genetic basis for the difference in phenotypic expression of the corneal proliferation and neovascularization. Identification of the responsible gene(s) will help clarify molecular mechanisms relating to these refractory clinical problems. Enhanced understanding of the biochemical and molecular biological mechanisms responsible for blindness caused by corneal neovascularization and surface disease is the first step towards more effective treatment of these related ocular diseases.